The greater incidence of hypertension and related cardiovascular diseases in men than in premenopausal women has become a serious problem. The difference may relate to exaggerated responses of the cardiovascular and the sympatho-adrenomedullary system (SAS) to stress. Estrogens (E) are protective: they attenuate both stress responsiveness in women, and the development of hypertension in rats. The SAS regulates cardiovascular function not only by releasing catecholamines (CA) but also neuropeptide Y (NPY) - a potent vasoconstrictor, cardiodepressant, and a neuromodulator. Sympathoneural (alone or Interacting with extraneuronal, platelet-derived) NPY is released into circulation during Intense SAS activation, and amplifies and prolongs adrenergic responses. We find that greater and more prolonged cardiovascular and SAS responsiveness to acute stress in male than in female rats is associated with increased release of and presser responses to NPY in males. It is not known whether sex differences In the cardiovascular responsiveness to stress relate to the actions of sex hormones on the peripheral SAS; In particular whether sex hormones differentially regulate synthesis and release of CA and NPY, and their receptors. The proposal will test the hypotheses that E attenuate, and/or testoserone facilitates, hemodynamic (systemic and regional) responses to acute and chronic stress through their Interactions with the peripheral SAS (adrenergic and NPY-mediated components). The experiments will establish the effects of sex hormones on 1/ in vivo hemodynamics; 2/ synthesis of NPY (NPY tissue content and in situ MRNA hybridization), and CA content in neuronal, extraneuronal, and adrenomedullary pools; 3/ sympatho-neural release of NPY and NE (isolated mesenteric bed); and 4/ NPY and adrenergic receptors and their interactions. As suggested by our preliminary studies, the possibility of sex hormonal regulation of these subtypes of adrenoceptors (alpha-2) and NPY receptors (Y2 and/or Yl) which are accessible to blood-borne substances (extrajunctional) will be assessed using membrane receptor binding and in vitro pharmacological studies. Finally, the hypothesis that gender and sex hormones Influence development of hypertension will be tested using stress-sensitive borderline hypertensive rats (BHR), which become fully hypertensive upon chronic exposure to stress. These studies will, for the first time, evaluate the role of a novel vasoconstrictor peptide, NPY, In sex differences. The longterm significance of this research Is that it increases the understanding of sexual dimorphism in cardiovascular regulation and adaptation to stress, and provides grounds for the development of new procedures for diagnosis and treatment of individuals at high risk for cardiovascular diseases.